In Vitro Fertilization (IVF) is a common intervention to assist couples suffering from childlessness. The first step in an IVF cycle, after any required hormonal stimulation of a female subject, is the retrieval, or aspiration, of oocytes. Hormone stimulation leads to an increased number of follicles being matured in the female. In a normal menstrual cycle, one to two oocytes are produced. In contrast, about 5 to 15 oocytes are generally matured in a successful IVF cycle. Today there is an increasing interest in using no or minimal hormone stimulation and instead to mature the oocytes after retrieval or to use a natural cycle in which the normally one or two matured oocytes are considered sufficient for the IVF procedure.
Independent of the method of hormone stimulation, each oocyte resides in a follicle. During an IVF procedure the follicles are emptied while still in the ovaries. This is normally done transvaginally which means that an oocyte retrieval needle is used to penetrate the vaginal wall and the ovaries. Following localization of the follicles by ultrasound, an oocyte retrieval needle is used to puncture and enter each follicle and then the follicular fluid containing the oocytes is retrieved by aspiration. The retrieval is achieved through an induced negative pressure. In cases where the oocytes are not released from the follicle through aspiration only, a pre-warmed flush solution may be used together with the aspiration to release the oocytes and to increase the aspirated fluid volume.
Oocyte retrieval needles used to empty follicles in vivo for the purpose of an IVF cycle may comprise a single or double lumen. Double lumen needles have a first lumen for retrieving oocytes from a follicle and a second lumen for concurrently flushing media into the follicle. This is believed, by some, to release oocytes from the follicle better than retrieval with a single lumen needle without flushing. However, it is more common to use a single lumen needle without flushing. Although a single lumen needle could be used to both retrieve and flush, it is not possible to use a single lumen needle to flush and aspirate at the same time. Therefore, when using a single lumen needle with flushing, there is a risk that the oocytes are flushed away instead of retrieved.
Oocyte retrieval needles marketed today are of uniform outer diameter (OD) and inner diameter (ID) along the full length of the needle. The most common needles are either 16 or 17 Gauge which correspond to an OD of 1.65 mm and 1.47 mm respectively. These needles are available from for example Cook Medical Inc. (Bloomington, Ind., USA), Smiths Medical International (Watford, UK) and Gynetics Medical Products N.V. (Achel, Belgium). Needles of 18 Gauge (1.27 mm OD) are available from Smiths Medical International.
The length of an oocyte retrieval needle varies, for example, depending on the type of needle guide used which in turn depends on the type of ultrasound transducer used. Typical total needle lengths are between 200 mm and 400 mm.
The inner diameter (ID), i.e. luminal diameter, of the oocyte retrieval needle must be larger than the diameter of the oocyte, which for a human is approximately 0.1 to 0.2 mm. The ID of the needle should also allow movement of the cumulus cell mass covering the oocytes. Production and material restraints affect how small the ID can be, as do the stress and friction induced on the oocytes within a thin needle.
The retrieval procedure normally takes about 10 to 30 minutes, mainly depending on how many follicles there are to penetrate and empty. Without anesthesia and sedation it is a rather difficult and, in some cases, very painful procedure for the female. Therefore it is standard in some countries to use general anesthesia during the procedure. However, the use of general anesthesia is associated with medical risks and the requirement of having an anesthetist present increases costs. Consequently, some countries, such as those in Scandinavia, perform oocyte retrieval under mild sedation and/or local anesthesia. The trend today is that more and more clinics are moving towards using mild sedation and/or local anesthesia as it is less costly and safer, although it creates more discomfort or pain for the female.
Needle manufacturers have responded to this change in procedure by producing thinner oocyte retrieval needles in order to cause less pain to the patient. A relationship has been found between the thickness of the needle and the pain felt by a subject (Aziz et al (1993) Human Reproduction 8(7):1098-1100). This study compared the use of two needle diameters: 16 and 18 gauge. A 16 gauge needle was used in one ovary and an 18 gauge needle was used in the other ovary. Use of a different needle in each ovary allowed the subject to be used as her own control. Mild sedation was used on the subjects and the pain was self assessed on a 0 to 5 scale. It was found that the thinner needle was significantly associated with less perceived pain.
Perceived pain and cramps are also problems following the oocyte retrieval procedure. In a study by Miller et al (2004) (Fertility and Sterility 81(1):191-193), self assessed pain and cramping was scored 30 minutes and 24 hours after the oocyte retrieval. This showed that there was pain and cramping both at 30 minutes and during the 24 hours following oocyte aspiration. There is no data at this time to confirm that pain and cramps after the aspiration procedure are actually reduced with a thinner needle, but as less tissue damage occurs with a thinner needle, this would be expected.
As mentioned above, thinner needles cause less trauma and bleeding than thicker needles. This is advantageous because trauma and bleeding may affect the implantation of the embryo. Implantation is generally carried out only two to six days after the retrieval of the oocyte, therefore any trauma caused during the retrieval process might prevent proper implantation.
However, the use of thinner needles also has several disadvantages as a thinner needle also has a narrower lumen. For example, the sample, e.g. an oocyte, might get stuck and/or harmed within the lumen of the thin needle. The approximate diameter of a human oocyte is 0.1 to 0.2 mm and, with the cumulus cells surrounding the oocyte, the whole cell mass can have a diameter as large as 10 mm (Aziz et al 1993). Therefore, the thinner the needle, the larger is the risk of damaging an oocyte as it travels through the needle. Consequently the use of a thinner needle increases the risk of harming the oocytes which could reduce the likelihood of an IVF procedure resulting in a successful pregnancy.
Another disadvantage of thinner needles is that, for application of a given negative pressure, aspiration through a thinner needle takes a longer time than through a thicker needle. The longer the sample (e.g. oocyte and follicular fluid) is in the needle, the longer it is subjected to room temperature and thus the sample cools down more. A thinner needle lumen also increases the contact area between the needle wall and the sample, which further cools down the sample. Some samples, e.g. oocytes, are very sensitive to temperatures below physiological temperature and lose viability as temperature drops.
An alternative to the longer aspiration time required for a thinner needle would be to increase the applied negative pressure to speed up movement of the follicular fluid through the needle. However, this has the disadvantage that the application of a higher pressure may stress and cause other physical damage to the sample. Application of too high a negative pressure is a common concern during oocyte aspiration as it might harm the zona pellucida of the oocyte. Also, an applied negative pressure can never exceed 1 atm (101.3 kPa), when working in a normal pressure environment. Furthermore, a thin needle also has the disadvantage of being more difficult for a user to manipulate as it is more likely to bend than a thicker needle.
Current oocyte retrieval needles will be discussed in relation to the following drawings FIGS. 1 to 5, in which, for ease of reference, like parts have been referred to by like reference numbers. Data providing results of comparisons of needles according to the present invention and other needles are given in FIGS. 6 to 10.
FIG. 1 is a schematic longitudinal cross section of a uterus and apparatus for ultrasound guided transvaginal aspiration of follicles from an ovary (prior art);
FIG. 2 is a schematic longitudinal cross section of a single lumen needle suitable for use with the apparatus shown in FIG. 1 (prior art);
FIG. 3 is a longitudinal cross section of a double lumen needle suitable for use with the apparatus shown in FIG. 1 (prior art);
FIG. 4 is a longitudinal cross section of a single lumen needle connected to a syringe, the single lumen needle being suitable for transvaginal aspiration of follicles from an ovary (prior art); and
FIG. 5 is a longitudinal cross section of a single lumen needle connected to a syringe via tubing, the single lumen needle being suitable for transvaginal aspiration of follicles from an ovary (prior art).
FIG. 1 shows a uterus (150) comprising the fundus (152), myometrium (154), vagina (156), fallopian tubes (160), ovaries (158) and ovarian follicles (104). Typical known apparatus (100) for ultrasound guided transvaginal aspiration of an ovarian follicle (104) is shown in situ. A single lumen oocyte retrieval needle (102) is introduced transvaginally into an ovarian follicle (104) containing the oocyte and is held on a needle guide (106) which in tum is held on an ultrasound transducer (108). The ultrasound transducer produces an ultrasound visual field of the follicles (109). The trailing end of the single lumen needle is connected to aspiration tubing (110) which in turn is connected to a test tube (112) for collection of follicular fluid containing the oocytes. A negative pressure is induced in the test tube (112) by application of a vacuum pump (not shown). The test tube (112) is sealed with a silicone stopper (114) with connectors (not shown).
The oocyte retrieval needle (102) may be a single lumen needle or a double lumen needle. A single lumen needle is shown in FIG. 2. A double lumen needle is shown in FIG. 3. Other aspiration needle configurations, each with a Luer connector and a syringe to induce negative pressure, are shown in FIGS. 4 and 5.
FIG. 2 shows a known single lumen needle apparatus (200) which comprises an oocyte retrieval needle (202). The trailing end of the needle (202) comprises a fingertip grip (222). The trailing end of the needle (202) is connected to aspiration tubing (210) which, in tum, is connected to a test tube (212) via a silicone stopper (214). The test tube (212) is connected to a vacuum pump (not shown), via the silicone stopper (214), a Luer connection (216) and vacuum tubing (218). Application of a vacuum to the vacuum tubing (218) causes fluid to be drawn into the needle (202) and consequently into the test tube (212) in the direction of arrow A.
FIG. 3 shows a known double lumen needle apparatus (300). The trailing end of the oocyte retrieval needle (302) comprises a fingertip grip (322). The trailing end of the needle (302) is connected to flush tubing (324). The distal end of the flush tubing (324) comprises a Luer connection (325) for connection to a source of flush media. The trailing end of the needle (302) is also connected to aspiration tubing (310) which in tum is connected to a test tube (312) for collection of the follicular fluid containing the oocytes. A negative pressure is induced in the test tube (312) by application of vacuum pump (not shown). The test tube (312) is connected to the vacuum pump (not shown), via a silicone stopper (314), a Luer connection (316) and vacuum tubing (318). Application of a vacuum to the aspiration tubing (318) causes fluid to be drawn into the needle (302) and consequently into the test tube (312) in the direction of arrow A. Flushing media may be flushed through the flushing tubing (324) into the needle (302) in the direction of arrow B.
FIG. 4 shows another known single lumen needle apparatus (400), which comprises, at the trailing end of the oocyte retrieval needle (402), a fingertip grip (422). The trailing end of the needle (402) is connected to a syringe (426) via a Luer connection (not shown). Withdrawal of the syringe plunger (428) from the syringe barrel (430) induces a negative pressure within the needle (402) and causes fluid to be drawn into the needle (402) and consequently into the syringe (426) in the direction of arrow A.
FIG. 5 shows a known alternative to the needle apparatus of FIG. 4. A single lumen needle apparatus (500) comprises a single lumen oocyte retrieval needle (502), at the trailing end of which is a fingertip grip (522). The trailing end of the needle (502) is connected to a syringe (526) via aspiration tubing (524) and a Luer connection (not shown). Withdrawal of the syringe plunger (528) from the syringe barrel (530) induces a negative pressure within the needle (502) and causes fluid to be drawn into the needle (502) and consequently into the syringe (526) in the direction of arrow A.
Previous inventions relating to needles include those described in WP2005/025434, US2005/0143619, U.S. Pat. No. 5,843,023, U.S. Ser. No. 6,979,339, U.S. Pat. No. 6,461,302 and U.S. Pat. No. 6,929,623. The needles described in WO2005/025434, US2005/0143619, U.S. Pat. No. 5,843,023, U.S. Ser. No. 6,979,339 and U.S. Pat. No. 6,461,302 are all constructed with uniform diameters. As such they either impose pain and/or tissue trauma on the female or they may induce stress and/or trauma to the oocyte. The use of a needle with a large inner diameter has an advantage in that it minimizes stress and/or trauma induced on the sample, e.g. oocyte, being retrieved and it works fast. Use of a needle with a small inner diameter has a disadvantage in that it results in a long retrieval, i.e. aspiration, time. A long retrieval time is inconvenient for the doctor carrying out the aspiration, inconvenient and uncomfortable for the subject from which the sample is being retrieved and increases the extent to which the sample cools and/or is otherwise stressed or traumatized during the retrieval procedure.
WO2005/025434 discloses an anesthetic needle for internal periovarial blocking in conjunction with egg retrieval.
US2005/0143619 discloses an ovum collection device comprising a handle, a collection needle extending from the handle and heating arrangement to maintain the collection needle at a selected temperature to prevent damage to the ovum being collected. Although this invention might solve the temperature issue during oocyte aspiration, it discloses a needle of uniform diameter and as such it has either the disadvantages of a needle with a small ID or a needle with a large OD, as discussed above.
U.S. Pat. No. 5,843,023 and U.S. Pat. No. 6,979,339 both disclose aspiration needle constructions with side ports. Both U.S. Pat. No. 5,843,023 and U.S. Pat. No. 6,979,339 disclose even sized needles that either has the disadvantages of a needle with a small ID or a needle with a large OD, as discussed above.
U.S. Pat. No. 6,461,302 discloses an ovum retrieval device for retrieving an ovum and follicular fluid from a follicle. The device comprises a needle connected to a means for inducing suction on the needle and therefore allowing a sample to be drawn into the needle.
U.S. Pat. No. 6,929,623 discloses a syringe comprising a needle having a first region with a wide diameter connected to a second region with a narrow diameter. The needle is used for delivery of, rather than for retrieval of, robust viscous liquids to ducts, such as the urethra, esophagus and blood vessels of a patient. There is no suggestion to use the needle to collect samples such as oocytes.